A Highly Regio- and Stereoselective Synthesis of α-Fluorinated Imides

Letter pubs.acs.org/OrgLett

A Highly Regio- and Stereoselective Synthesis of α‑Fluorinated Imides via Fluorination of Chiral Enamides Yan-Shuang Xu,† Yu Tang,*,† He-Jing Feng,† Ji-Tian Liu,† and Richard P. Hsung*,‡ †

School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery and High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, Tianjin University, Tianjin, 300072, P. R. China ‡ Division of Pharmaceutical Sciences, School of Pharmacy, and Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53705, United States S Supporting Information *

ABSTRACT: A highly π-facial selective and regioselective fluorination of chiral enamides is described. The reaction involves an enantioselective fluorination exclusively at the electron-rich enamide olefin with N−F reagents such as Selectfluor and N-fluoro-benzenesulfonimide [NFSI] accompanied by trapping of the β-fluoro-iminium cationic intermediate with water. The resulting N,O-hemiacetal could be oxidized using Dess-Martin periodinane, leading to an asymmetric sequence for syntheses of chiral α-fluoro-imides and optically enriched α-fluoro-ketones. Scheme 1. Stereoselective Synthesis of α-Fluoro-imides

T

he importance of organo-fluorine compounds has been abundantly validated through a broad range of applications in medicinal chemistry and drug development1 as well as material2 and agrochemical sciences.3 The incorporation of fluorine and/or fluorine-containing groups into an organic compound has often provided agents and materials with unique chemical, physical, and biological properties.4 One of the major synthetic challenges in fluoro-organic chemistry is to asymmetrically construct fluorinated stereogenic carbon centers. Differding5 demonstrated the first stoichiometric asymmetric fluorination of β-ketoester enolates with a chiral N−F (N-fluoroamine) reagent in 1988. Given the number of impressive examples of enantioselective fluorinations being reported over the past decade,6 asymmetric fluorinations represent an area of immense interest from the synthetic community. In relevance to our work, Davis7 reported an elegant synthesis of α-fluoro-imides using enolate derived from chiral imide 1 substituted with chiral oxazolidinone auxiliary8 (1 → 2 in Scheme 1). Our longstanding interest in the chemistry of enamides has drawn us to develop stereoselective fluorination methods using chiral enamides,9 which has remained elusive. Such an approach in combination with an oxidative process (3 → 4) would represent a complementary approach to Davis’ asymmetric approach to αfluoro-imides. With the nitrogen atom being substituted with an electronwithdrawing functionality, chiral enamides possess superior stability to their enamine counterparts, while maintaining excellent reactivities. This is evident by their recent emergence as another powerful chiral building block in organic synthesis.10,11 In particular, chiral enamides have been employed in highly regio- and/or stereoselective Diels−Alder cycloadditions,12 [2 + 2] cycloadditions,13 cyclopropanation,14 © 2015 American Chemical Society

epoxidation,15 and halo-etherification.16 We wish to report here a highly regio- and stereoselective fluorination of chiral enamides for the synthesis of chiral α-fluoro-imides and optically enriched α-fluoro-ketones. Our efforts commenced with exploring the right fluorination conditions using chiral enamide 3a as the testing enamide, and with Selectflur,17 N-fluoropyridinium triflate [Py-F],18 and Nfluoro-benzenesulfonimide [NFSI]19 as the fluorinating agent. When reactions were carried out in CH3CN at 40 °C, we found that it was faster with Selectflur (entry 1 in Table 1) and much slower with Py-F (entry 2), and that NFSI was the best N−F reagent20 in terms of diastereoselectivity, leading to α-fluoroimides 4a and 4a′ as an isomeric mixture in 57% yield after DMP oxidation (entry 3).21 We note here that attempts to directly Received: December 13, 2014 Published: January 12, 2015 572

DOI: 10.1021/ol503591d Org. Lett. 2015, 17, 572−575

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Table 1. Optimization of the Fluorination Conditionsa

entry

solvent

reagenta

time [h]

yield [%]b [dr]c

1 2 3 4 5 6 7 8 9e

CH3CN CH3CN CH3CN anhyd CH3CNd 2.0 equiv H2O in CH3CN 1% H2O in CH3CN 2% H2O in CH3CN 5% H2O in CH3CN 2% H2O in CH3CN

Selectfluor Py-F NFSI NFSI NFSI NFSI NFSI NFSI NFSI

0.5 24 9.5 8 8 12 12 31 6

29 [57:43] 26 [61:39] 57 [89:11] 95:5] 61 [>95:5] 65 [>95:5] 69 [95:5] 59 [>95:5] 53 [>95:5]

a Isolated yields. bThe diastereomeric ratio [dr] was determined by 1H or/and 19F NMR spectroscopy.

Table 2. Effect of the Chiral Auxiliary on Selectivitya

which a variety of different R substituents were evaluated, excellent diastereoselectivities of >92:8 and moderate-to-good yields were obtained. It is noteworthy that while electrondonating and -withdrawing substitution groups at the aryl does not influence diastereoselectivity, with a strong electronwithdrawing group, reactions indeed took a much longer time (see entry 3). Lastly, although predictable, these asymmetric fluorinations can indeed be highly regioselective in favor of the electron-rich enamide-olefin as demonstrated with fluorinations of chiral enamides 7 and 9 (Scheme 2). While synthetically this method represents a stereoselective approach for constructing chiral α-fluoro-imides, mechanistically, this fluorination provides some insight into the chemistry of chiral enamides. On the basis of the observed stereochemical outcome, a proposed mechanistic model is shown in Scheme 3. We had calculated that the most stable conformation of these chiral enamides has the chiral oxazolidinone ring essentially coplanar with the alkene to maximize the delocalization of the nitrogen lone pair into the olefin.24 With this conformational preference, the chiral oxazolidinone auxiliary plays a distinct role

Reaction condition: 1.1 equiv of NFSI, 2% H2O in CH3CN, 40 °C; and then, DMP, NaHCO3, CH2Cl2, rt. bIsolated yields. cDiastereomeric ratios [dr] were determined by 1H or/and 19F NMR spectroscopy. a

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N,O-hemiacetal intermediate from fluorinations of disubstituted enamides. We have reported an asymmetric synthesis of α-fluoro-imides via fluorinations of chiral enamides. The reaction involves selectively fluorinating the electron-rich enamide olefin using Selectfluor and N-fluoro-benzenesulfonimide [NFSI] followed by trapping of a β-fluoro-iminium cationic intermediate with water and oxidation of the resulting N,O-hemiacetal. From a practical perspective, the reaction is operationally simple, requires inexpensive reagents and mild conditions, and provides chiral α-fluoro-imides and optically enriched α-fluoro-ketones in good yields and high selectivities.

Scheme 2. A Regioselective Fluorination

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Scheme 3. A Proposed Stereochemical Model

ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures as well as NMR spectra, characterizations, and X-ray structural files (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

in providing a key facial bias for the fluorine to approach from the Si-face as represented in ent-3d. Subsequent trapping of the Nacyl iminium ion A with water can in principle be stereoselective, but this stereochemical information is lost in the ensuing oxidation. On the other hand, for Z-enamides such as 3e, the predicted selectivity would be poor based on this conformational model. To alleviate the allylic strain shown in 3e, the chiral oxazolidinone ring needs to rotate away and can no longer be coplanar with the alkene, thereby leading much less differentiated π-faces [see C]. To support this model, we prepared Z-enamide 3e and found that not only is the yield of its fluorination inferior to those of E-enamides but also the diastereoselectivity is diminished significantly. Lastly, as a useful synthetic application, we examined asymmetric fluorinations of trisubstituted enamides. As shown in Scheme 4, optically enriched 2-fluorocyclohexanone 1325

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ACKNOWLEDGMENTS R.P.H. thanks the NIH (GM66055) for funding. Y.T. thanks the National Natural Science Foundation of China (Nos. 21172169 and 21172168) and The National Basic Research Project (No. 2014CB932201) for generous funding. We also thank Dr. HaiBin Song of the Nankai University for providing X-ray structure and data analysis.

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REFERENCES

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Scheme 4. Fluorinations of Trisubstituted Enamides

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